Hussain I. Saba

Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study

Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters.

Redefinition of Cutaneous Lymphatic Drainage With the Use of Lymphoscintigraphy for Malignant Melanoma

Lymphoscintigraphy was performed on 82 patients with melanoma registered at the University Melanoma Clinic. From these data, precise lymphatic drainage basins could be drawn for the head, neck, shoulder, and trunk. These drawings differed significantly from the classic anatomic studies, providing a functional look at the cutaneous lymphatic drainage. This new method correlates much better with clinical experiences and demonstrates much larger areas of ambiguous drainage than previously reported. Data from the lymphoscintigrams also emphasize the individuality of cutaneous lymphatic flow. The implications of these data in planning elective node dissections for intermediate thickness melanomas are obvious, since it is estimated that up to 59% of the dissections for trunk and head and neck primary melanomas may be misdirected if based on classic anatomic studies. The data indicate that all patients with head, neck, and shoulder lesions should undergo lymphoscintigraphy to define possible drainage basins at risk for metastatic disease. Similarly, truncal lesions require scintigrams except when they are within four well-defined areas with an extremely low probability of ambiguous drainage. Lesions in these areas show very reliable and predictable drainage to a single nodal group.

Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.

Alterations in platelet concentration and aggregation in normal pregnancy and preeclampsia

Platelets were evaluated in normal pregnant women and in pregnant subjects with mild and severe preeclampsia, nonpregnant control subjects, and pregnant subjects with chronic hypertension. The parameters studied included platelet count, presence of circulating platelet aggregates, and in vitro platelet aggregability by means of a variety of agonists of platelet aggregation. When subjects with a normal pregnancy were compared to nonpregnant controls, they demonstrated a significantly lower platelet count and an increase in circulating platelet aggregates and in vitro hypoaggregability. Significant differences among the groups of pregnant subjects could not be found. These studies suggest the occurrence of platelet activation in pregnancy. This activation causes in vivo platelet aggregation followed by exhaustion of platelets.

Endotoxin-mediated inhibition of human platelet aggregation

A variety of endotoxins, when added to human platelet-rich plasma (PRP) or to suspensions of washed platelets (WP), demonstrated an inhibitory effect on platelet aggregation induced by various aggregating agents. Endotoxin blocked the release of 14C serotonin from platelets but had no influence on cyclic AMP production. Endotoxin did not interfere with thromboxane generation by platelets. However, endotoxin-treated platelets failed to respond to added thromboxane. The inhibitory effect of endotoxin on platelet aggregation was more pronounced in the presence of ionophore A23187 as compared to other aggregating agents and was effectively reversed by calcium but not by magnesium, another divalent cation. Furthermore, endotoxin failed to inhibit the ristocetin-induced agglutination of formaldehyde-fixed platelets; a non-calcium dependent phenomenon. These findings appear to suggest that endotoxin-mediated inhibitory activity of platelet aggregation is related to the interference in the role of calcium. The antiaggregatory activity of endotoxin appears to be due to a direct and rapid action on platelets and not due to a non-specific binding, as the effect was not abolished by washing the endotoxin-incubated platelets. Endotoxin-mediated alteration of platelet function may contribute to bleeding diathesis in septecemic and endotoxemic patients.

Metastatic melanoma with an unknown primary.

An infrequent initial presentation for malignant melanoma is the diagnosis of metastatic disease without a history of an obvious primary lesion. Confusion exists in the literature concerning the workup, treatment, and prognosis of the unknown primary melanoma. A retrospective, computer-aided chart review of 580 consecutively registered patients with melanoma at the University Treatment Center (Tampa, FL), identified 18 patients with an unknown primary presentation. There were 10 males and 8 females with a mean age of 38.4 years. Ninety-four percent of the patients were diagnosed with metastatic disease in a nodal basin, whereas 1 patient had a resected isolated lung mass as the initial presentation. In the patients who presented after having a biopsy of a single positive node for diagnosis, more disease was recovered in the nodal basin with a formal node dissection in 59% of the patients. Actuarial survival curves were constructed for the group with unknown primary melanoma. As a control population, survival curves were constructed of the subpopulation of patients with melanoma who had a known primary and had stage III (regional nodal disease) at diagnosis. There was no difference in survival between those with known and unknown primary melanoma (p = 0.96).

Lithium carbonate in patients with small cell lung cancer receiving combination chemotherapy.

Lithium administration has been shown to attenuate the leukopenia associated with systemic chemotherapy. The results of a randomized trial of lithium in 45 patients with small cell lung cancer who received combination chemotherapy and radiation therapy are reported. Patients randomized to receive lithium were started on 300 mg three times daily for 18 days of every 21 day chemotherapy cycle. Patients who received lithium experienced significantly less mid-cycle leukocyte and neutrophil count depression and spent fewer days with leukopenia and neutropenia than control patients regardless of age or extent of disease. Patients who received lithium spent fewer days hospitalized and fewer days with fever in the presence of severe neutropenia than control patients. The cumulative risk of fever with signs of infection was greater in control patients regardless of age, disease extent or the presence of marrow involvement. Patients who were given lithium received significantly more chemotherapy than control patients. Patient survival was greatest in those with limited disease, in complete responders and in those who received more than 75 percent of their induction chemotherapy although it did not differ between the two study groups. The majority of patients required either reduction or discontinuation of lithium. Those who received lithium continuously demonstrated a higher objective response rate and longer survival than either patients in whom the lithium had to be discontinued or those randomized to the control group. Infection was an important cause of death in the control group and cardiovascular event occurred frequently in the lithium group, but the major cause of death in this patient population remains progressive malignant disease.

Myelodysplastic syndromes in the elderly: The role of growth factors in management

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous clonal bone marrow disorders leading to peripheral cytopenia(s) and hypercellular marrow in the majority of the patients. The morphology of the cell lines is characterized by dysplastic features in some or all cell lines. The FAB classification has divided MDS in five subgroups, namely (1) RA (refractory anemia); (2) RARS (refractory anemia with ring sideroblasts); (3) CMML (chronic myelomonocytic leukemia); (4) RAEB (refractory anemia with excess blasts); and (5) RAEB-T (refractory anemia with excess blasts in transformation). Myelodysplastic syndrome remains primarily a disease of the elderly. With a reported median age of 74.4 years, patients have a chronic relentless course with complication of cytopenias, and a significant number of MDS patients, especially from the RAEB and RAEB-T categories, end up in acute myeloid leukemic transformation. Cytogenetic abnormalities are present in 40-58% of the cases and can provide not only help in diagnosis, but also understanding regarding the clinical course and prognostic aspect. Management of MDS is quite pragmatic and at this stage far from satisfactory. Various modalities have included use of differentiating agents, aggressive chemotherapy, bone marrow transplant and, more recently, significant interest has been generated in the use of hematopoietic growth factors. Differentiating agent trials have been unrewarding so far; chemotherapy trials have resulted in less benefit and more early toxic deaths, especially in the elderly MDS patients where the disease predominates. Bone marrow transplant appears suitable for some patients who are at a younger age. Salvation from this disease is being searched in the proper usage of hematopoietic growth factors and cytokines. There has been concern, however, that usage of growth factors has led to early and enhanced transformation of these patients to frank acute leukemic states. This concept appears to be somewhat refuted by newer controlled trials with GM-CSF and G-CSF, emphasizing that the acute leukemic transformation is the natural course of the disease and is not hastened by growth factor use. Preliminary studies are also suggesting that a combination of growth factors, especially G-CSF and erythropoietin as compared to chemotherapies, could be more beneficial in prolonging the survival of MDS patients who have progressed to the acute leukemic phase. More studies are needed for the understanding of the pathogenetic mechanism(s) in order to facilitate a more suitable and appropriate management strategy for MDS.

The Evaluation of Putative Tumor Markers for Malignant Melanoma

Biomarkers have long held out the promise that malignancies might be diagnosed early and that patients could be monitored more confidently during their clinical course to more reliably predict recurrence and the effect of therapy. Reliable tumor markers have been described for colon carcinoma, hepatomas, and other tumors, but no reliable marker has been identified to monitor the course of malignant melanoma. Recently, the plasma level of lipid-bound sialic acid (LASA-P) has been described as reflecting an alteration in the surface membrane of cancer cells. An attempt was made to correlate the LASA-P level, along with the serum level of neuron-specific enolase, a glycolytic enzyme specific to cells of neuroectoderm origin including melanocytes, with clinical disease activity with a follow-up to at least 2 years. Two hundred seventy patients had blood samples drawn at various times during their clinical course for assay of LASA-P and neuron-specific enolase. Eighty of the patients (30%) sampled developed a recurrence sometime during their clinical course, whereas another 10 patients had active disease noted at diagnosis with evaluative tumor markers. The sensitivity and specificity of neuron-specific enolase was 27% and 77%, respectively, and cannot be recommended as a marker for melanoma. LASA-P showed a sensitivity of 65%, with 55 patients recurring and having active disease with abnormally high markers and 35 patients recurring or having active disease with normal markers. Specificity of the LASA-P test was 76%. When recurrence was associated with elevated LASA-P levels, the elevated level preceded recurrence by a median of 9.3 months. LASA-P may be a useful marker to follow patients with malignant melanoma.

Isolated limb perfusion for recurrent melanoma of the extremity.

Recent reports in the literature suggest that hyperthermic isolated limb perfusion (HILP) may be effective in preventing local recurrence in patients with deeply invasive melanoma or in patients with recurrent disease confined to the extremity. It has been used in the past as an adjuvant treatment after resection of the primary melanoma or recurrence, or as a therapeutic measure if all the disease on the extremity cannot be resected. A prospective, nonrandomized trial of 16 patients with melanoma with recurrent disease confined to the extremity underwent HILP. The protocol involved the wide local excision of all recurrent disease when possible, elective or therapeutic node dissection when indicated, and HILP using cisplatin. In 11 patients in whom all recurrent disease could be resected and the HILP was considered prophylactic, only 1 patients disease has recurred in the perfusion circuit. Before the perfusion, the 11 patients had a total of 19 local or intransit recurrences. Of the 5 patients in whom all recurrent disease could not be resected, disease persisted in 4 patients. When compared with a concurrent control population of patients with extremity melanoma who had a local recurrence and were not perfused, the patients with melanoma who underwent HILP had a significant prolongation of disease-free survival (p less than 0.05), but a similar actuarial survival. In this study, we demonstrate that HILP can prevent local regional recurrences in patients with metastatic melanoma who are at high risk for further recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)